Re-establishment of blood flow in blocked human arteries by transferring nano-encapsulated drug through medical devices, designed for the same and releasing the nano-encapsulated drug in human artery with body ph

ABSTRACT

A drug-delivering insertable medical device for treating a medical condition associated with a body lumen is disclosed. The drug-delivering insertable medical device includes an outer surface coated with two or more nano-carriers having two or more average diameters. A nano-carrier of the two or more nano-carriers has an average diameter suitable for penetrating one or more layers of two or more layers of the body lumen. The nano-carrier includes a drug surrounded by an encapsulating medium. The encapsulating medium includes one or more of a biological agent, a blood excipient, and a phospholipid.

FIELD OF THE INVENTION

The invention generally relates to a medical device for administrating adrug to a target site in a body lumen. More specifically, the inventionrelates to a drug-delivering insertable medical device coated withnano-carriers of one or more drugs for efficient delivery of the one ormore drugs across various layers of a blood vessel.

BACKGROUND OF THE INVENTION

Stents and other medical devices are used for re-establishment of aproper blood flow in a blocked artery in interventional cardiologicalprocedures, such as, percutaneous transluminal coronary angioplasty.However, the existing interventional cardiological procedures andcardiological medical devices used in these procedures are associatedwith phenomenon like restenosis. In order to reduce the instances ofrestenosis that occur following angioplasty procedures or stentdeployment Drug Eluting Stents (DESs) are often used. The current DESsare loaded with drugs with the help of polymers. The polymers maytrigger inflammation at a site where the DESs are implanted. In certaininstances, the inflammation triggered by the DESs may be more severethan the inflammation that is caused by bare metal stents owing to thepresence of polymers in the DESs. The inflammation triggered by thepolymers may in turn lead to thrombus formation because of body'sphysiological immune response. The thrombus thus formed may be an acutethrombus or a sub-acute thrombus. The thrombus may further aggravateresulting into blockage of the artery. In addition, the DESs withnon-degradable polymers are associated with late inflammation reactions,thereby resulting in late thrombus formation. Thus, the polymers usedfor loading the drugs on the DESs may lead to restenosis.

In order to avoid the inflammation that is associated with the use ofthe polymers for loading the drug on the stent, the drug may be loadedon surface of the stent without using polymers. However, the methods forloading the drug on the surface of the stent without using the polymersthat are known in the art are based on modifying the surface of thestent.

In addition, the presence of one or more drugs and the polymers on aninner surface of the stent results in a delayed healing or an improperhealing of the lesions as compared to the bare metal stents. A long-termanti-platelet (e.g. Clopidrogel) therapy is generally advised inpatients with the delayed healing or the improper healing. Theanti-platelet therapy is also associated with side effects and thus isnot advisable for long-term.

Further, the particle sizes of the drugs as well as the polymers thatare coated on the DESs are larger than the sizes of the tissue pores ata target site. Therefore, a substantial amount of the drugs remainunabsorbed. The unabsorbed drugs may get washed away in blood stream andmay produce side effects. For example, currently used DESs are loadedwith more than 100 micro-grams of a drug out of which, only 12 nanogramto 25 nanogram of the drug penetrates the tissues of the artery. Rest ofthe drug is either washed away in the blood stream from the innersurface of DESs or is released over time.

Further, the currently used DESs are associated with phenomenon likefocal restenosis and edge restenosis. One of the major reasons for focalrestenosis is that some portions of the lesion are adequately suppliedwith the drug by the DESs while some portions of the lesion (region notcovered by the DES) are very poorly or not at all supplied with the drugby the DESs. The portions of the lesion that are adequately suppliedwith the drug may possibly remain less prone to restenosis as comparedwith the portions of the lesion that are poorly supplied or not at allsupplied with the drug.

In the current DESs, the drug is coated on the metal surface. The amountof the drug that reaches the lesion is generally equal to a metal toartery ratio. The metal to artery ratio for the current DESs generallyranges from 10% to 20%. Thus, only 10% to 20% of the lesion is suppliedwith the drug. Whereas, the remaining 80% to 90% of the lesion is eithervery poorly supplied with the drug or not at all supplied with the drug.Further, owing to a larger particle size of the drug coated on thesurface of the DESs, an optimum diffusion of the drug into the tissuesof an artery is not achieved. The diffusion of the drug into the tissuesof the artery further depends on properties of the drug. For example,sirolimus eluting stents exhibit a poor diffusion of sirolimus into thetissues of the artery because of low solubility associated withsirolimus. Therefore, sirolimus eluting stents may exhibit focalrestenosis that is as high as 71% of the total restenosis. Whereas,paclitaxel eluting stents may exhibit focal restenosis that is as highas 56% of the total restenosis. Additionally, most of the drugs that areadministered to a patient using the current DESs are hydrophobic innature and have less affinity for body tissues. As a result, a highamount of the drug needs to be loaded in the DESs for achieving thedesired therapeutic effect.

Therefore, there is a need in the art for an improved drug-deliveringinsertable medical device associated with reduced instances of focalrestenosis, edge restenosis, total restenosis, acute thrombus formation,sub-acute thrombus formation, late thrombus formation, delayed healingof lesions, and improper healing of lesions. Further, an improveddrug-delivering insertable medical device is needed in the art that mayreduce the duration of anti-platelet therapy otherwise advised topatients with the delayed healing of lesions and/or the improper healingof lesions post deployment of the DES. In addition, an improved drugreleasing medical device that provides for enhanced bioavailability ofthe drugs, enhanced biocompatibility and delivery of a drug to maximumportion of a lesion in the blood vessel with optimum drug loading isalso needed in the art.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 illustrates the size distribution of nano-particles of soyaphospholipid as detected by Malvern ZS90 in accordance with Example 1.

FIG. 2 illustrates the size distribution of nano-carriers as detected byMalvern ZS90 in accordance with Example 1.

FIG. 3 illustrates a chromatogram for the standard solution inaccordance with Example 2.

FIG. 4 illustrates a chromatogram for the sample solution the standardsolution in accordance with Example 2.

FIG. 5 illustrates a chromatogram for the aqueous solution ofnano-carriers in accordance with Example 3.

FIG. 6 illustrates the percent sirolimus release from the coated stentsystem for Day 1 to Day 39, in accordance with Example 4.

DETAILED DESCRIPTION OF THE INVENTION

Before describing in detail embodiments that are in accordance with theinvention, it should be observed that the embodiments reside primarilyin combinations of components of a medical device for treating a medicalcondition associated with a body lumen. Accordingly, the components havebeen described to include only those specific details that are pertinentto understanding the embodiments of the invention so as not to obscurethe disclosure with details that will be readily apparent to those ofordinary skill in the art having the benefit of the description herein.

In this document, the terms “comprises”, “comprising” or any othervariation thereof, are intended to cover a non-exclusive inclusion, suchthat a process, method, article, or apparatus that comprises a list ofelements does not include only those elements but may include otherelements not expressly listed or inherent to such process, method,article, or apparatus. An element preceded by “comprises . . . a” doesnot, without more constraints, preclude the existence of additionalidentical elements in the process, method, article, or apparatus thatcomprises the element.

Further, before describing in detail embodiments that are in accordancewith the invention, it should be observed that all the scientific andtechnical terms used herein for describing the invention have samemeanings as would be understood by a person skilled in the art.

In addition, before describing in detail embodiments that are inaccordance with the invention, it should be observed that adrug-delivering insertable medical device may be a medical device thatmay be inserted or implanted in a body lumen for delivering a drug to atarget site in the body lumen. The drug-delivering insertable medicaldevice may be one of, for example, a stent, a balloon, a stent mountedon a balloon (a pre-crimped stent) and a balloon catheter. Thedrug-delivering insertable medical device may be any other medicaldevice used for performing percutaneous transluminal angioplastyprocedures that may deliver nano-carriers of the drug to the target sitewithout departing from the scope of the invention.

The stent may be one of, for example, an endovascular stent, aperipheral vascular stent, a urethral stent, a prostatic stent, a stentgraft, a permanently implantable stent, a temporarily implantable stent,and a stent made up of, one or more of one or more of, but not limitedto, a metal, an alloy, a biodegradable polymer, and a non-degradablepolymer, SS316L, L605 cobalt-chromium alloy, and nickel-titanium alloy,and any stent that may be coated with the nano-carriers of the drug.Additionally, the stent may be any stent coated with one or more of, butnot limited to, a biodegradable polymer, a biocompatible polymer abioerodable polymer and a non-degradable polymer.

The balloon may be any balloon made up of an elastomeric material thatmay be inflated using suitable inflating means in the percutaneoustransluminal angioplasty procedures and that may be coated with thenano-carriers of the drug for delivering the two or more nano-carriersto the target site in the body lumen. The balloon may be one of, forexample, an angioplasty balloon and any other balloon used forinterventional cardiovascular procedures.

The pre-crimped stent may be a stent mounted on a balloon such that thepre-crimped stent may be coated with the nano-carriers of the drug whenthe stent is mounted on the balloon. The pre-crimped stent may furtherinclude two of more of, the balloon, the stent mounted on the balloon, ashaft and a hypotube.

Further, the drug-delivering insertable medical device may one of, forexample, a spinal implant, a percutaneous implant, a transdermal drugdelivery device, a dental implant, any surgical implant, and a medicaldevice that may be inserted into a human body for delivery of one ormore drugs at a particular site in a human body.

It should be observed that, hereinafter, the nano-carriers of the drugmay also be referred to as one or more of, nano-carriers, a first set ofnano-carriers, a second set of nano-carriers, a third set ofnano-carriers and two or more nano-carriers.

Generally speaking, pursuant to various embodiments, a drug-deliveringinsertable medical device for treating a medical condition associatedwith a body lumen is disclosed. The medical condition may be one of,restenosis, blocked body lumen, atherosclerosis, myocardial infarctionand plaque accumulation in the body lumen. The body lumen can be forexample, a blood vessel a urethra, an esophagus, a ureter and a bileduct.

The drug-delivering insertable medical device includes an outer surfacecoated with two or more nano-carries. The outer surface of thedrug-delivering insertable medical device comes in direct contact with atarget site in the body lumen when the drug-delivering insertablemedical device is inflated or expanded upon positioning at the targetsite. A nano-carrier of the two or more nano-carriers includes a drugsurrounded by an encapsulating medium. As the drug is surrounded by theencapsulating medium, the surface of the nano-carriers is devoid of thedrug. The encapsulating medium includes one or more of a biologicalagent, a blood excipient and a phospholipid. The two or morenano-carriers have two or more average diameters. The nano-carrier ofthe two or more nano-carriers has an average diameter suitable forpenetrating one or more layers of two or more layers of the body lumen.When the drug-delivering insertable medical device comes in proximity toa target site in the body lumen, the two or more nano-carriers arereleased from the outer surface. Thereafter, the nano-carrier of the twoor more nano-carriers penetrates the one or more layers of the two ormore layers of the body lumen based on the average diameter. Thus, asize-dependent penetration of the nano-carrier across the one or morelayers of the two or more layers of the body lumen is achieved.

In an embodiment, the drug-delivering insertable medical device isemployed for a treating a medical condition associated with a bloodvessel. The blood vessel may be one of, for example, a coronary artery,a peripheral artery, a carotid artery, a renal artery, an illiac artery,arteries below a knee, and a vein. The blood vessel includes two or morelayers of the tissues. The two or more layers of the tissues include anintima layer, a media layer and an adventitia layer. The intima layerincludes an innermost layer of tissues of the blood vessel that is indirect contact with the blood flow through the blood vessel. The medialayer includes a layer of tissues of the blood vessel that is beneaththe intima layer. Whereas, the adventitia layer includes a layer oftissues of the blood vessel that is beneath the media layer.

The outer surface of drug-delivering insertable medical device is coatedwith the two or more nano-carriers. In an exemplary embodiment, when apre-crimped stent is used as the drug-delivering insertable medicaldevice, the outer surface such as one or more portions of an abluminalsurface of the pre-crimped stent and one or more portions of the balloonthat are exposed through the pre-crimped stent are coated with two ormore nano-carriers. According to various embodiments, only the outersurface of the drug-delivering insertable medical device is coated withthe two or more nano-carriers.

Whereas, the inner surface of the drug-delivering insertable medicaldevice is substantially devoid of the two or more nano-carriers.Accordingly, in an exemplary embodiment, when the drug-deliveringinsertable medical device is a stent, only the abluminal surface of thestent is coated with the two or more nano-carriers. Whereas, the luminalsurface of the stent is substantially devoid of the two or morenano-carriers. Such selective coating of the outer surface may minimizethe instances of delayed healing.

Accordingly, when the drug-delivering medical device comes in proximityof the blood vessel, a nano-carrier of the two or more nano-carriers maypenetrate one or more of the intima layer, the media layer and theadventitia layer based on an average diameter associated with thenano-carrier. A nano-carrier penetrates one or more of the intima layer,the media layer and the adventitia layer by passing through one or moreof inter-tissue pores present in the intima layer, a vasa vasorumassociated with the media layer and a vasa vasorum associated with theadventitia layer. The inter-tissue pores present in the intima layer,the vasa vasorum associated with the media layer and the vasa vasorumassociated with the adventitia layer have different internal diameters.Therefore, penetration of the nano-carrier of the two or morenano-carriers into one or more of the intima layer, the media layer andthe adventitia layer depends upon the average diameter associated withthe nano-carrier.

The two or more nano-carriers coated on the outer surface of thedrug-delivering medical device have two or more average diameters. Thetwo or more average diameters may range from 1 nm to 5000 nm.

In an embodiment, the drug-delivering medical device may be coated witha first set of nano-carriers, a second set of nano-carriers, and a thirdset of nano-carriers. The first set of nano-carriers has a first averagediameter suitable for penetrating the intima layer through theinter-tissue pores present in the intima layer. The second set ofnano-carriers have a second average diameter suitable for penetratingthe media layer through the vasa vasorum associated with the media layerand the inter-tissue pores present in the intima layer. The third set ofnano-carriers have a third diameter suitable for penetrating theadventitia layer through the inter-tissue pores present in the intimalayer, the vasa vasorum associated with the media layer and the vasavasorum associated with the adventitia layer.

In an embodiment, the first average diameter may range from 800 nm to1500 nm, the second average diameter may range from 300 nm to 800 nm andthe third average diameter may range from 10 nm to 300 nm. In anotherembodiment, the first average diameter is 1000 nm, the second averagediameter is 700 nm and the third average diameter is 200 nm. The firstaverage diameter, the second average diameter and the third averagediameter may be varied to meet a particular therapeutic need withoutdeparting from the scope of the invention.

The two or more nano-carriers coated on the drug-delivering medicaldevice may include 10% to 60% of the first set of nano-carriers, 20% to60% of the second set of nano-carriers and 30% to 80% of the third setof nano-carriers. Alternatively, the two or more nano-carriers may becoated to include about 15% to 90% of the first set of nano-carriers,10% to 85% of the second set of nano-carriers and 5% to 85% of the thirdset of nano-carriers.

Accordingly, when the drug-delivering medical device comes in proximityto the target site in the blood vessel, the two or more nano-carrierscorresponding to one or more of the first set of nano-carriers, thesecond set of nano-carriers, and the third set of nano-carriers arereleased from the outer surface of the drug-delivering insertablemedical device. Subsequently, the two or more nano-carriers thusreleased penetrate the one or more layers of the blood vessel based onrespective average diameters associated with the two or morenano-carriers. Thus, a size dependent penetration of the two or morenano-carriers is achieved.

In addition to the size dependent penetration of the two or morenano-carriers, a rate at which a nano-carrier is released from the outersurface of the drug-delivering medical device is also controlled withthe help of an average diameter of the nano-carrier. A nano-carrier witha small average diameter is rapidly released by the drug-deliveringmedical device. Therefore, time required for the third set ofnano-carriers to release from the outer surface upon coming in proximityof the target site is less than the time required for the second set ofnano-carriers and the first set of nano-carriers to get released fromthe outer surface. Thus, the third set of nano-carriers exhibit a rapidrate of release from the outer surface. Whereas, the second set ofnano-carriers and the third set of nano-carriers exhibit slower rates ofrelease from the outer surface as compared with the rate of release ofthe third set of nano-carriers.

Once the two or more nano-carriers are released and are penetratedacross the one or more layers of the blood vessel, the drug is releasedfrom the two or more nano-carrier into one or more of the adventitialayer, the media layer and the intima layer. The drug is released whenthe encapsulating medium is dissolved. Thus, an in-tissue release of thedrug at the target site is achieved. Further, one or more nano-carriersthat penetrate into the adventitia layer may remain in the adventitialayer for a prolonged time. In other words, the adventitia layer may actas a reservoir of the drug from where the drug is slowly released overthe prolonged time.

Additionally, the drug may further diffuse across the one or more of theadventitia layer, the media layer and the intima layer during theprolonged time. In such an instance, the drug that is diffused acrossthe one or more of the adventitia layer, the media layer and the intimalayer may provide an in-tissue diffusion of the drug for the prolongedtime. Thus, because of the in-tissue release of the drug and in-tissuediffusion of the drug, a maximum portion of lesions at the target siteis supplied with the drug. Therefore, the probable chances of focalrestenosis are reduced as compared with the conventional DESs.

In addition, because of the in-tissue release of the drug and thein-tissue diffusion of the drug for the prolonged time, the instances ofdelayed healing and improper healing of the lesions at the target siteare minimized as compared with the conventional DESs. As a result, ananti-platelet therapy that has to be given to the patients with delayedhealing and/or improper healing of the lesions may also be minimized.

Further, as the encapsulating medium includes one or more of abiological agent, a blood excipient and a phospholipid, the two or morenano-carriers exhibit an affinity for the tissues of the target site.Such an affinity facilitates efficient transferring of the two or morenano-carriers from the outer surface of the drug-delivering insertablemedical device to the target site over a time. As a result,substantially each of the first set of nano-carriers, the second set ofnano-carriers, and the third set of nano-carriers are released from theouter surface over the time. Thereafter, the outer surface of thedrug-delivering insertable medical device may become substantiallydevoid of the two or more nano-carriers over the time. In an exemplaryembodiment, where the drug-delivering insertable device is a stent, thestent may become substantially devoid of the two or more nano-carrierswithin 7 to 45 days after deployment of the stent at the target site. Inanother exemplary embodiment, the stent may become substantially devoidof the two or more nano-carriers within about 30 days of deployment ofthe stent.

In addition, the encapsulating medium also keeps the surface of thenano-carrier devoid of any free drug. This facilitates in avoiding adirect contact of the drug with the surface of the drug-deliveringinsertable medical device. Further, the drug comes in contact with thetissues of the target site only when the nano-carrier penetrates intothe one or more layers of the blood vessel and the encapsulating mediumis dissolved. Thus, direct exposure of the drug to the tissues of thetarget site and the surface of the drug-delivering insertable medicaldevice is prevented.

The drug may include nano-crystals of the drug. The nano-crystals of thedrug may have an average diameter ranging from 1 nm to 5000 nm. Further,the nano-crystals of the drug may have two or more different averagediameters. Alternatively, the drug may be one or more of, nano-sizedparticles, nano-spheres, liposomes, nano-capsules, dendrimers, and anyother similar form of the drug that has nano-dimensions. The drug may beone or more of, but are not limited to, an anti-proliferative agent, ananti-inflammatory agent, an anti-neoplastic agent, an anti-coagulantagent, an anti-fibrin agent, an antithrombotic agent, an anti-mitoticagent, an antibiotic agent, an anti-allergic agent and an antioxidant,an anti-proliferative agent, estrogens, a protease inhibitor,antibodies, an immunosuppressive agent, a cytostatic agent, a cytotoxicagent, a calcium channel blocker, a phosphodiesterase inhibitor, aprostaglandin inhibitor, a dietary supplement, vitamins, anti-plateletaggregating agent and genetically engineered epithelial cells.

The drug may be one or more of, for example, but are not limited to,sirolimus, paclitaxel, tacrolimus, clobetasol, dexamethasone, genistein,heparin, 17 beta-estadiol, rapamycin, everolimus, ethylrapamycin,zotarolimus, ABT-578, Biolimus A9, docetaxel, methotrexate,azathioprine, vincristine, vinblastine, fluorouracil, doxorubicinhydrochloride, mitomycin and analogs thereof, miomycine, sodium heparin,a low molecular weight heparin, a heparinoid, hirudin, argatroban,forskolin, vapiprost, prostacyclin, a prostacyclin analogue, dextran,D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa,recombinant hirudin, bivalirudin, nifedipine, colchicines, lovastatin,nitroprusside, suramin, a serotonin blocker, a steroid, a thioproteaseinhibitor, triazolopyrimidine, a nitric oxide or nitric oxide donor, asuper oxide dismutase, a super oxide dismutase mimetic, estradiol,aspirin, angiopeptin, captopril, cilazapril, lisinopril, permirolastpotassium, alpha-interferon, bioactive RGD and any salts or analoguesthereof.

The drug is surrounded by the encapsulating medium. The encapsulatingmedium may be one or more of, a biological agent, a blood excipient anda phospholipid. Alternatively, the encapsulating medium may be one ormore of, one or more biological agents, one or more blood excipients,one or more phospholipids and one or more excipients. The biologicalagent may include nano-particles of the biological agent. Thenano-particles of the biological agent may have an average diameterranging from 1 nm to 5000 nm. Further, the nano-particles of thebiological agent may have two or more different average diameters.Alternatively, the biological agent may include one or more of,nano-sized particles, nano-spheres, liposomes, nano-capsules,dendrimers, and any other similar form of the biological agent that hasnano-dimensions.

The biological agent may be one or more of, but are not limited to, drugcarriers, excipients, blood components, excipients derived from blood,naturally occurring phospholipids, solid lipid nano-particles,phospholipids obtained from a living animal, synthetically derivedphospholipids, lipoids, vitamins and sugar molecules. The biologicalagent may be, for example, but are not limited to, steroids, vitamins,estradiol, esterified fatty acids, non esterified fatty acids, glucose,inositol, L-lactate, lipoproteins, carbohydrates, tricalcium phosphate,precipitated calcium phosphate, calcium phoshate tribasic, substancesderived from at least one of human, egg and soybean, phospholipon 80H,phospholipon 90H, Lipoids S75, Lipoids E80, Intralipid 20, Lipoid EPC,Lipoid E75, lipids obtained from egg, lipids obtained from soya,phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol,phosphatidylserine, phosphatidic acid, cardiolipin, andphosphatidylethanolamine.

The phospholipid may include nano-particles of the phospholipid. Thenano-particles of the phospholipid may have an average diameter rangingfrom 1 nm to 5000 nm. Further, the nano-particles of the phospholipidmay have two or more different average diameters. Alternatively, thephospholipid may include one or more of, nano-sized particles,nano-spheres, liposomes, nano-capsules, dendrimers, and any othersimilar form of the phospholipid that has nano-dimensions. Thephospholipid may include one or more of, but are not limited to, lipidsobtained from egg, lipids obtained from soya, phosphatidylcholine,phosphatidylglycerol, phosphatidylinositol, phosphatidylserine,phosphatidic acid, cardiolipin, and phosphatidylethanolamine.

The blood excipient may include nano-particles of the blood excipient.The nano-particles of the blood excipient may have an average diameterranging from 1 nm to 5000 nm. Further, the nano-particles of the bloodexcipient may have two or more different average diameters.Alternatively, the blood excipient may include one or more of,nano-sized particles, nano-spheres, liposomes, nano-capsules,dendrimers, and any other similar form of the blood excipient that hasnano-dimensions. The blood excipient may be one or more of, but are notlimited to, steroids, vitamins, estradiol, esterified fatty acids,non-esterified fatty acids, glucose, inositol, L-lactate, lipids,lipoproteins, phospholipid, carbohydrates, tricalcium phosphate,precipitated calcium phosphate, and calcium phoshate tribasic.

The blood excipient and the biological agent are soluble at a pH below7.4. Therefore, when the two or more nano-carriers come in contact withthe tissues of the target site, the biological agent and the bloodexcipient get dissolved in the blood. The dissolution of the biologicalagent and the blood excipient results in the release of the drug fromthe two or more nano-carriers at the target site. Thus, a pH dependentrelease of the drug from the two or more nano-carriers is achieved.

In an exemplary embodiment, the drug-delivering insertable medicaldevice is a coronary stent. The coronary stent is, for example, ChromiumCobalt L-605 stent. The coronary stent includes an abluminal (outer)surface coated with the two or more nano-carriers. The two or morenano-carriers include a first set of nano-carriers with an averagediameter of about 1200 nm, the second set of nano-carriers with anaverage diameter of about 700 nm and the third set of nano-carriers withan average diameter of about 200 nm. When the stent comes in proximityof the target site the two or more nano-carriers are released from theabluminal surface of the stent. Thereafter, the first set ofnano-carriers penetrates the intima layer through the inter-tissue porespresent in the intima layer. The second set of nano-carriers penetratethe media layer through the vasa vasorum associated with the media layerand the inter-tissue pores present in the intima layer. The third set ofnano-carriers penetrate the adventitia through the vasa vasorumassociated with the adventitia layer, the vasa vasorum associated withthe media layer and the inter-tissue pores present in the intima layer.

In another exemplary embodiment, the drug-delivering insertable medicaldevice is a balloon. The balloon is, for example, an ultrathinangioplasty balloon. The balloon includes an outer surface coated withthe two or more nano-carriers. The two or more nano-carriers include afirst set of nano-carriers with an average diameter of about 1200 nm,the second set of nano-carriers with an average diameter of about 700 nmand the third set of nano-carriers with an average diameter of about 200nm. When the balloon is inflated upon coming in proximity of the targetsite the two or more nano-carriers are released from the abluminalsurface of the stent. Thereafter, the first set of nano-carrierspenetrates the intima layer through the inter-tissue pores present inthe intima layer. The second set of nano-carriers penetrates the medialayer through the vasa vasorum associated with the media layer and theinter-tissue pores present in the intima layer. The third set ofnano-carriers penetrates the adventitia through the vasa vasorumassociated with the adventitia layer, the vasa vasorum associated withthe media layer and the inter-tissue pores present in the intima layer.The balloon may be coated with the two or more nano-carriers when theballoon is in a folded configuration or an unfolded configuration.

In yet another exemplary embodiment, the drug-delivering insertablemedical device is a pre-crimped stent (a stent mounted on a balloon).For example, the pre-crimped stent is a Chromium Cobalt L-605 stentmounted on an ultrathin angioplasty balloon. The pre-crimped stent iscoated with the two or more nano-carriers. A nano-carrier of the two ormore nano-carriers coated on the pre-crimped stent includesnano-crystals of sirolimus encapsulated with nano-particles of one ormore of soya phospholipid and tricalcium phosphate. The two or morenano-carriers include a first set of nano-carriers with average diameterof 1200 nm, a second set of nano-carriers with average diameter of 700nm and a third set of nano-carriers with average diameter of 200 nm.

An outer surface of the pre-crimped stent is coated with the two or morenano-carriers when the stent is mounted on the balloon. One or moreportions of the balloon that are not covered by the stent (one or moreportions of the balloon that are exposed through one or more struts ofthe sent) are also coated with the two or more nano-carriers along withthe abluminal surface of the stent. As the luminal surface of the stentis covered by the balloon, only the abluminal surface of the stent iscoated with the two or more nano-carriers. When the pre-crimped stentcomes in proximity to the target site, the balloon is inflated. Theinflation of the balloon causes an expansion of the stent. In responseto the inflation of the balloon and the expansion of the stent at thetarget site in the coronary artery, the two or more nano-carriers arereleased from the pre-coated stent. The two or more nano-carriers coatedon the one or more portions of the balloon provide for a burst releaseof the one or more nano-carriers from the balloon. Whereas, the two ormore nano-carriers coated on the abluminal surface of the stent providefor controlled release of the two or more nano-carriers from theabluminal surface of the stent.

Additionally, the outer surface of the pre-crimped stent may include aportion of the balloon that extends longitudinally beyond one or more ofa distal boundary and a proximal boundary of the stent. In such a case,a portion that longitudinally extends at least 0.05 mm beyond one ormore of the distal boundary of the stent and the proximal boundary ofthe stent may also be coated with the two or more nano-carriers. Coatingthe portion that longitudinally extends at least 0.05 mm beyond thedistal boundary of the stent or/and the proximal boundary of the stentwith the two or more nano-carriers, provides for delivery of the drug tothe lesions present beyond the distal boundary and/or proximal boundaryof the stent. Thus, probable chances of edge restenosis followingdeployment of the stent in a subject may be minimized.

In still yet another exemplary embodiment, a pre-crimped stent (a stentmounted on a balloon) is coated with two or more layers of the two ormore nano-carriers. An outer layer of the two or more layers coated onthe balloon and the stent includes the third set of nano-carriers.Whereas, an inner layer of the two or more layers coated on the balloonand the stent includes one or more of the first set of nano-carriers andthe second set of nano-carriers. The third set of nano-carriers presentin the outer layer on the balloon and the stent provide for burstrelease of the third set of nano-carriers when the pre-crimped stentcomes in proximity to the target site. Whereas, the one or more of thesecond set of nano-carriers and the first set of nano-carriers presentin the inner layer provide for a controlled release of the one or moreof the second set of nano-carriers and the first set of nano-carriersfrom the pre-crimped stent.

In an embodiment, the drug-delivering insertable medical device includesan outer surface coated with two or more layers of the two or morenano-carriers. The two or more nano-carriers present in an outer layerof the two or more layers include a first set of drugs. Whereas, two ormore nano-carriers present in an inner layer of the two or more layersinclude a second set of drugs. The second set of drugs may include oneor more drugs that are different from one or more drugs present in thefirst set of drugs. The first set of drugs may include for example, butnot limited to, one or more of an anti-inflammatory agent and ananti-thrombotic agent. The first set of drugs being present in the outerlayer will provide for burst release. Thus, first set of drugs may bedelivered to the target site to control the inflammation or injury thatmay be caused by the drug-delivering insertable medical device. Whereas,the second set of drugs may include for example, but not limited to, ananti-proliferative agent. The second set of the drugs that is present inthe inner layer is released from the outer surface after the outer layeris released. Thus, the second set of drugs may be delivered over aperiod of time to control the proliferative phase of the inflammationcell cycle.

One or more of the first set of drugs and the second set of drugs may beselected from one or more of, but are not limited to, an anti-neoplasticagent, an anti-coagulant agent, an anti-fibrin agent, an antithromboticagent, an anti-mitotic agent, an antibiotic agent, an anti-allergicagent and an antioxidant, estrogens, a protease inhibitor, antibodies,an immunosuppressive agent, a cytostatic agent, a cytotoxic agent, acalcium channel blocker, a phosphodiesterase inhibitor, a prostaglandininhibitor, a dietary supplement, vitamins, anti-platelet aggregatingagent and genetically engineered epithelial cells without departing fromthe scope of the invention.

In another embodiment, the drug-delivering insertable medical device iscoated with three layers of the two or more nano-carriers. An inner-mostlayer of the three layers of the two or more nano-carriers includes aprohealing agent. A middle layer of the three layers includes ananti-proliferative agent and an outer-most layer of the three layersincludes one or more of an anti-inflammatory agent and ananti-thrombogenic agent. The outer-most layer provides for burst releaseof the two or more nano-carriers. Thus, the outer-most layer thatcontains one or more of the anti-inflammatory agent and theanti-thrombogenic agent may address the inflammation. The middle layerthat contains the anti-proliferative agent releases the two or morenano-carriers after the two or more nano-carriers of the outer-mostlayer are released. Thus, the middle layer may address the proliferativephase of the inflammation cell cycle at the target site. Whereas, theinner-most layer releases the two or more nano-carriers after the two ormore nano-carriers of the middle layer are released. Thus, theinner-most layer that contains the prohealing agent may be helpful inpromoting extracellular matrix formation at the target site therebyaddressing the regeneration phase of the inflammation cell cycle. Thus,the drug-delivering insertable medical device may be designed to addressthe various phases of the inflammation cell cycle at the target site.

Generally speaking, pursuant to various embodiments, the invention alsodiscloses a method for treating a medical condition associated with abody lumen. The medical condition may be one of, restenosis, blockedbody lumen, atherosclerosis, myocardial infarction and plaqueaccumulation in the body lumen. The body lumen may be, for example, ablood vessel, a urethra, an esophagus, a ureter and a bile duct. In anembodiment, the method includes delivering two or more nano-carriers toa target site in the blood vessel by using a drug-delivering insertablemedical device having an outer surface coated with two or morenano-carriers.

The method further includes positioning the drug-delivering insertablemedical device at a target site in the blood vessel. Thereafter, thedrug-delivering insertable medical device is expanded or inflated. Inresponse to expanding or inflating the drug-delivering insertablemedical device, the outer surface of the drug-delivering insertablemedical device comes in contact with the target site and the two or morenano-carriers are released from the outer surface. The two or morenano-carriers thus released then penetrate one or more of the two ormore layers of the blood vessel depending upon respective averagediameters associated with the two or more nano-carriers.

A nano-carrier of the two or more nano-carriers includes a drugsurrounded by an encapsulating medium. The encapsulating medium includesone or more of a biological agent, a blood excipient and a phospholipid.In accordance with various embodiments, the drug may includenano-crystals of the drug. Whereas, the biological agent, thephospholipid and the blood excipient may include nano-particles of thebiological agent, the phospholipid and the blood excipient,respectively. The nano-crystals of the drug, the nano-particles of thebiological agent, the nano-particles of the phospholipid and thenano-particles of the blood excipient may be obtained by conventionalmethods. Alternatively, the nano-crystals of the drug, nano-particles ofthe biological agent, the nano-particles of the phospholipid and thenano-particles of the blood excipient available in the market may alsobe used. For example, one or more of the nano-crystals of the drug, thenano-particles of the biological agent, the nano-particles of thephospholipid and the nano-particles of the blood excipient may beobtained by using one or more of, but are not limited to, high-pressurehomogenization, spray drying, high speed homogenization, ball milling,pulverization, sol-gel methods, hydrothermal methods, spray pyrolysismethod and the like.

A nano-carrier is obtained by encapsulating the nano-crystals of thedrug by the nano-particles of one or more of the biological agent, thephospholipid, and the blood excipient by using methods known in the art.The nano-carrier thus obtained may have an average diameter ranging from1 nm to 5000 nm.

In an embodiment, a first set of the nano-crystals of the drug with anaverage diameter of 1200 nm, a second set of the nano-crystals of thedrug with an average diameter of 700 nm and third set of thenano-crystals of the drug with an average diameter of 200 nm areobtained using one or more methods known in the art. Further, a firstset of the nano-particles of the biological agent with an averagediameter of 1200 nm, the second set of the nano-particles of thebiological agent with an average diameter of 700 nm and the third set ofthe nano-particles of the biological agent with an average diameter of200 nm are obtained using one or more methods known in the art.

Thereafter, a solution of the first set of the nano-crystals of thedrug, a solution of second set of the nano-crystals of the drug and asolution of the third set of the nano-crystals of the drug are obtainedby using a suitable solvent. Similarly, a solution of the first set ofthe nano-particles of the biological agent, a solution of second set ofthe nano-particles of the biological agent and a solution of the thirdset of the nano-particles of the biological agent are obtained by usinga suitable solvent.

Subsequently, the solution of the first set of nano-crystals of the drugand the solution of the first set of the nano-particles of thebiological agent are subjected to an encapsulation process to obtain afirst set of nano-carriers with a first average diameter. Similarly, thesolution of the second set of nano-crystals of the drug and the solutionof the second set of the nano-particles of the biological agent aresubjected to an encapsulation process to obtain a second set ofnano-carriers with a second average diameter. Whereas, the solution ofthe third set of nano-crystals of the drug and the solution of the thirdset of the nano-particles of the biological agent are subjected to anencapsulation process to obtain a third set of nano-carriers with athird average diameter.

The first set of nano-carriers, the second set of nano-carriers and thethird set of nano-carriers thus obtained are then coated as one or morelayers on an outer surface of the drug-delivering insertable medicaldevice using the methods known in the art.

In an exemplary embodiment, a solution of the first set of thenano-carriers, a solution of the second set of the nano-carriers and thethird set of the nano-carriers may be obtained using a suitable solvent.Thereafter, the solution of the first set of the nano-carriers, thesolution of the second set of the nano-carriers and the solution of thethird set of the nano-carriers may be coated on the outer surface of thedrug-delivering insertable medical device using a coating machine knownin the art.

The coating machine may have a rotatable mandrel. The drug-deliveringinsertable medical device may be mounted on the rotatable mandrel androtated along with the rotatable mandrel. The outer surface of thedrug-delivering insertable medical device may be exposed to theatomization nozzle. Thereafter, one or more of the solution of the firstset of the nano-carriers, the solution of the second set of thenano-carriers and the solution of the third set of the nano-carriers maybe sprayed on the outer surface to obtain the drug-delivering insertablemedical device coated with one or more of the first set ofnano-carriers, the second set of nano-carriers and third set ofnano-carriers.

The coating machine may have one or more reservoirs for storing thesolution of the first set of the nano-carriers, the solution of thesecond set of the nano-carriers and the solution of the third set of thenano-carriers. For example, the solution of the first set of thenano-carriers, the solution of the second set of the nano-carriers andthe solution of the third set of the nano-carriers may be stored inthree different reservoirs. Alternatively, the solution of the first setof the nano-carriers, the solution of the second set of thenano-carriers and the solution of the third set of the nano-carriers maybe stored as a mixture in a single reservoir. The one or more reservoirsmay supply one or more of the solution of the first set of thenano-carriers, the solution of the second set of the nano-carriers andthe solution of the third set of the nano-carriers to an atomizationnozzle. The atomization nozzle may be used to spray the solution of thefirst set of the nano-carriers, the solution of the second set of thenano-carriers and the solution of the third set of the nano-carriers onthe surface of the drug-delivering insertable medical device.

In another embodiment, the two or more nano-carriers are coated as twolayers on the outer surface of the drug-delivering insertable medicaldevice. The drug-delivering insertable medical device is prepared byspraying, for example, the solution of the third set of thenano-carriers on the outer surface. Subsequently, the drug-deliveringinsertable medical device may be dried. Thereafter, one or more of thesolution of the second set of the nano-carriers and the solution of thefirst set of the nano-carriers may be sprayed on the outer surface.Subsequently, the drug-delivering insertable medical device may bedried. Thus, the drug-delivering insertable medical device with twolayers of the two or more nano-carriers may be obtained.

Thereafter, the drug-delivering insertable medical device coated withtwo or more nano-carriers is inserted into the blood vessel using acatheter assembly. The catheter assembly may include a guide wire, acatheter, a balloon, a stent mounted on the balloon and an inflationmechanism for inflating the balloon. The guide wire is advanced in theblood vessel to pass just a small distance beyond the target site. Thecatheter with the stent and the balloon mounted on a distal end of thecatheter is then advanced over the guide wire in such a way that thestent mounted on the balloon is positioned at the target site. Once thestent mounted on the balloon reaches the target site in the bloodvessel, the balloon is inflated using the inflation mechanism. Uponinflation of the balloon, the stent mounted on the balloon also expandsand an outer surface of the stent and a portion of the balloon exposedthrough the stent come in contact with a wall of the blood vessel at thetarget site. When the balloon comes in contact with the target site, thetwo or more nano-carriers coated on the balloon are released from theballoon and get delivered to the target site. Thereafter, the balloon isdeflated and withdrawn from the blood vessel, leaving the stent at thetarget site. The stent at the target site may release the two or morenano-carriers at the target site in the blood vessel over a prolongedtime. The two or more nano-carriers thus released then penetrate one ormore of the two or more layers of the blood vessel depending upon theirrespective average diameters associated.

In instances, the medical device may include a stent mounted on aballoon. The stent mounted on the balloon may be exposed to theatomization nozzle and may be sprayed with the solution of the two ormore nano-carriers. Thus, one or more portions of the balloon that isnot covered by the stent (one or more portions of the balloon exposedthrough the struts of the stent) are also coated with the two or morenano-carriers. The one or more portions of the balloon that are coatedwith the two or more nano-carriers provides for rapid release of the twoor more nano-carriers from the drug-delivering insertable medical deviceto the target site. Whereas, the two or more nano-carriers that arecoated on the outer surface of the stent provide for delayed release ofthe two or more nano-carriers from the outer surface of thedrug-delivering insertable medical device to the target site.

EXAMPLE 1

Soya phospholipid was obtained from Lioid GMBH, Batch No.: 776114-1/906.Sirolimus was obtained from Fujan Chemicals, China with purity greaterthan 99.5%. The water, other solvents and reagents used were of HPLCgrade. Amazonia Croco® (Chromium cobalt coronary L-605 stent systemmounted on ultrathin angioplasty balloon, hereinafter “the stentsystem”) was obtained from Minvasys, Paris, France.

Soya phospholipid (20 mg w/w) was added to de-ionized water (10 ml)followed by Tween 80 (5 mg) to obtain aqueous solution of soyaphospholipid. The aqueous solution of soya phospholipid (10 ml) wassubjected to a high speed homogenization at 15000-20000 rpm for 20 to 25minutes in ice-cold water bath to obtain Solution A1. The Solution A1thus obtained contained nano-particles of soya phospholipid. Thesolution A1 was subsequently analyzed for particle size detection usingMalvern ZS90 (Malvern, UK) size detector. FIG. 1 illustrates the sizedistribution of nano-particles of soya phospholipid as detected byMalvern ZS90. The average diameter of the nano-particles of the soyaphospholipid was found to be 475.79 nm.

Sirolimus (20 mg w/w) was added to 10 ml of de-ionized water to obtainaqueous solution of sirolimus. The aqueous solution of sirolimus (10 ml)was subjected to a high speed homogenization at 15000-20000 rpm for 150to 200 minutes in ice-cold water bath to obtain Solution A2. TheSolution A2 thus obtained contained nano-crystals of sirolimus. Thesolution A2 was subsequently analyzed for particle size detection usingMalvern ZS90 (Malvern, UK) size detector.

Solution A1 was gradually (drop by drop) added to Solution A2 and wassubjected to a high speed homogenization at 15000-20000 rpm for 20minutes to obtain 20 ml Solution A3. Solution A3 was again homogenizedfor 10 minutes. Solution A3 was then stirred with a magnetic stirrer(2MLH hot plate heater cum stirrer, Accumax, INDIA) for 20 minutes.Solution A3 thus obtained contained nano-carriers (nano-crystals ofsirolimus surrounded by nano-particles of soya phospholipid). SolutionA3 was subsequently analyzed for particle size detection using MalvernZS90 (Malvern, UK) size detector. FIG. 2 illustrates the sizedistribution of nano-carriers as detected by Malvern ZS90. The averageparticle size was found to be 410 nm.

Solution A3 (Aqueous solution of nano-carriers) was further subjected toextraction with dichloromethane. Solution A3 (20 ml) was transferred to100 ml separating funnel. 50 ml of dichloromethane was added to the 100ml separating funnel. The resultant mixture was shaken for 15 min andthen allowed to stand. Thereafter, two layers i.e. aqueous layer and thedichloromethane layer were observed in the 100 ml separating funnel. Thedichloromethane layer was separated from the aqueous layer. Thedichloromethane layer i.e. solution of the nano-carriers was stored inamber colored small measuring flask with batch number. Subsequently, thesolution of the nano-carriers was used for coating the stent system.

The solution of the nano-carriers (5 ml) was fed into the reservoir of acoating machine. The stent system was mounted on a rotating mandrel ofthe coating machine. The stent system was exposed to the atomizationnozzle of the coating machine. The stent system was rotated at 5 to 40rpm by rotating the mandrel and simultaneously the solution ofnano-carriers was sprayed over the stent system at 0.5-4.0 psi inert gaspressure and 2 oscillations. Thus the stent system coated with thenano-carriers (hereinafter “the coated stent system”) was obtained. Thestent system was removed and checked under high resolution microscopefor the coating surface smoothness and any foreign particles. The coatedstent system was then subjected to further analysis as explained inExample 2 below.

EXAMPLE 2

Detection of Drug Content of the Stent System:

The amount of sirolimus loaded on the coated stent system was calculatedusing HPLC analysis. The HPLC operating parameters were selected as:Flow Rate was set at 1.2 ml/min. (±0.01), λ Maxima was set at 278 nm (±1nm), Column Temperature was set at 60° C. (±2° C.), Sensitivity ofdetector was set at 0.02 AUFS and Analysis Time was set up to 20minutes.

HPLC System [LC-10ATVP pump (SHIMADZU, JAPAN)] attached with UV-VISDetector [SPD-10AVP (SHIMADZU, JAPAN)] and Rheodyne integrator[Analytical Technologies, Analytical 2010] was used for the HPLCanalysis. Column—C₁₈ [RP₁₈ Length 4.6 mm×250 mm, particle size 5 μm] wasattached with column oven [PCI] for the heating. 25 μl HamiltonMicro-syringe was used for injecting the samples. The samples werefiltered through the millipore PTFE 0.45-micron syringe filter beforeanalysis to avoid any particulate matters. Pre-calibrated class A gradevolumetric flasks were used. Amber colored glassware was used to protectagainst light. All the Renchem solvents and reagents used in theanalysis were of HPLC grade. Sirolimus was used as received from FujanChemicals, China with purity greater than 99.5%.

Mobile phase included Acetonitrile: Methanol: Water in a concentrationratio of 45:40:15. Mobile phase was subsequently degassed in anultrasonic cleaner for 10 minutes.

Sirolimus (0.5 mg) was taken in a clean and dry 10 ml Standard MeasuringFlask (SMF). The SMF was then filled up to the mark with the mobilephase and shaken for 5 to 10 minutes. The SMF was then kept in anultrasonic cleaner and degassed for 10 minutes. The solution was thenfiltered through 0.45 micron syringe filter to obtain the standardsolution with “Standard Concentration” of 50 μg/ml.

Using the micro-syringe, 20 μL of the standard solution was injected inthe HPLC injector and a chromatogram for the standard solution wasobtained. FIG. 3 illustrates a chromatogram for the standard solution.Subsequently, the area of the peak for the standard solution (“StandardArea”) was calculated. The retention time for the standard solution wasfound to be 3.732 minutes and the “Standard Area” corresponding to thepeak for the standard solution was found to be 3196.970 mV*Sec.

For the quantification of the drug content loaded on the stent system,the sample solution was prepared by inserting the coated sent system in10 ml SMF filled with methanol (10 ml). The SMF was then kept inultrasonic bath for 10 minutes to allow the sirolimus present in thecoated stent system to completely dissolve in the methanol. Thus, thesample solution was obtained.

Using the micro-syringe, 20 μL of the sample solution was injected inthe HPLC injector and a chromatogram for the sample solution wasobtained. FIG. 4 illustrates a chromatogram for the sample solution.Subsequently, the area of the peak for the sample solution (“SampleArea”) was calculated. The retention time for the sample solution wasfound to be 3.470 minutes and the “Sample Area” corresponding to thepeak for the sample solution was found to be 683.235 mV*Sec.

Subsequently, the amount of sirolimus present in the coated stent systemwas calculated using the following formula:Amount of Drug=(Sample Area/Standard Area)*(StandardConcentration/Sample Concentration)

Therefore, Amount of Drug=(683.235/3196.970)*(50/(1/10))=106.82 μg

Thus, the Amount of Drug loaded on the coated stent system was found tobe 106.85 μg.

EXAMPLE 3

Encapsulation Efficiency (EE)

1 ml of the aqueous solution of nano-carriers (Example 1) was taken in10 ml SMF. The volume was adjusted to 10 ml. 20 μL of the aqueoussolution of nano-carriers was injected in the HPLC injector and achromatogram for the aqueous solution of nano-carriers was obtained.FIG. 5 illustrates a chromatogram for the aqueous solution ofnano-carriers. The retention time for the aqueous solution ofnano-carriers was found to be 4.308 minutes and the “Area for AqueousSolution of Nano-carriers” corresponding to the peak for the aqueoussolution of nano-carriers was found to be 280.555. The amount of freedrug was calculated using the following formula:Amount of Free Drug=(Area for Aqueous Solution of Nano-carriers/StandardArea)*(Concentration of standard/Concentration of Aqueous Solution ofNano-carriers)

Thus, Amount of Free Drug(Sirolimus)=(280.555/3196.970)*(50/(1/10))=43.52. Therefore, the Amountof Free Drug in 1 ml of the Aqueous Solution of Nano-carriers was foundto be 43.87 μg. Thus, the Amount of Free Drug present in 20 ml would be877.4 μg. Subsequently, the % Encapsulation Efficacy was calculatedusing the following formula:% EE=(Initial Weight of Drug (mg)−Free Amount of Drug(mg))*100/(InitialWeight of Drug (mg))% EE=(20−0.8774)*100/20=95.61%.

Thus, the % encapsulation efficacy was found to be 95.61%.

EXAMPLE 4

The release of sirolimus from the coated stent system was studiedin-vitro by using Phosphate Buffer Saline (PBS) with 6.4 pH. The PBSsolution was prepared by dissolving 1.79 g of disodium hydrogenorthophosphate, 1.36 g of potassium hydrogen orthophosphate and 7.02 gof sodium chloride in 1000 ml HPLC grade water. The solution was kept inultrasonic cleaner for 10 minutes for dissolution.

Three cylindrical vials of 1.5 ml each were filled with freshly preparedPBS. The three vials were designated as, 15 seconds, 60 seconds andDay 1. The 15 seconds vial, 60 seconds vial and Day 1 vial were kept inincubator at 37° C. (+1° C.) for 60 minutes.

The coated sent system was then deepen in the 15 seconds vial and movedup and down for 15 seconds. Thereafter, the coated stent system wastransferred to the 60 seconds vial and inflated therein. The inflatedstent was kept in the 60 seconds vial for 60 seconds and then waswithdrawn from the 60 seconds vial. Subsequently, the coated sent systemwas then introduced in the Day 1 vial and placed in incubator for 24hours.

The PBS solution from the 15 seconds vial, the 60 seconds vial and theDay 1 vials were transferred to a different separating funnel. Equalamount of methanol (5 ml) was added to all three separating funnelsfollowed by addition of dichloromethane (10 ml). All the threeseparating funnels were shaken well for 10 minutes and then allowed tostand. Thereafter, the organic phase containing methanol,dichloromethane and sirolimus was separated and subjected to HPLCanalysis. Similarly, the coated stent assembly was analyzed for Day 2 toDay 39 by keeping the coated sent assembly for 24 hours each day into acorrespondingly marked vial under incubation. The amount of sirolimuspresent in each vial was determined and the percentage in-vitro releaseof sirolimus was calculated for Day 1 to Day 39. FIG. 6 illustratespercent sirolimus release from the coated stent system for Day 1 to Day39. The 15 second vial represented drug lost in transit duringangioplasty process. The 60 second vial represented burst release at Day1 while Day 2 vial to Day 39 vial represented programmed release ofsirolimus from the coated stent assembly. It was concluded that by endof Day 39 about 80% of sirolimus was released from the coated stentassembly.

EXAMPLE 5

Four animals were selected. Each animal of the four animals wasimplanted with three stents. The three stents included the stent systems(two) and one stent system without sirolimus. QCA results of theimplantation and follow-up were analyzed to give the mean luminaldiameters of the stented segments prior to the implantation, after theimplantation and at 28 days follow-up. The QCA results were used tocalculate stent/artery ratio, the acute gain, percent recoil and lateloss. The late loss in case of the stent system without sirolimus (BMS)is generally about 1 mm to 1.5 mm. While the late loss in case of thestent systems were found to be 0.45 mm (±0.23 mm). No death associatedwith the stent systems was reported. Further, thrombosis or restenosisassociated with the stent systems was also not reported in any of thefour animals. Thus, it was concluded that the stent systems areefficacious and safe as compared with the stent system without sirolimusor the BMSs. In the same study 28 day experiments showed averageneointimal thickness of about 150 (±15) microns in the DES and 185 (±50)micron in the excipients coated stents. The qualitative analysis showedcomplete healing of the neointima in all sirolimus coated stents.

Various embodiments of the invention provide a drug-deliveringinsertable medical device coated with different average sizednano-carriers of one or more drugs for efficient delivery of the one ormore drugs across various layers of a blood vessel. The invention alsoprovides a drug-delivering insertable medical device that exhibitsenhanced bioavailability and biocompatibility of the one or more drugs,which in turn results in a small loading dose of the one or more drugsonto the drug-delivering insertable medical device. The drug-deliveringinsertable medical devices in accordance with the invention isassociated with reduced instances of edge restenosis, focal restenosis,total restenosis, sub-acute thrombus formation, late thrombus formation,delayed healing of lesions and improper healing of lesions otherwiseassociated with the current DESs.

Those skilled in the art will realize that the above-recognizedadvantages and other advantages described herein are merely exemplaryand are not meant to be a complete rendering of all of the advantages ofthe various embodiments of the invention.

In the foregoing specification, specific embodiments of the presentinvention have been described. However, one of ordinary skill in the artappreciates that various modifications and changes can be made withoutdeparting from the scope of the present invention as set forth in theclaims below. Accordingly, the specification and figures are to beregarded in an illustrative rather than a restrictive sense, and allsuch modifications are intended to be included within the scope of thepresent invention. The benefits, advantages, solutions to problems, andany element(s) that may cause any benefit, advantage, or solution tooccur or become more pronounced are not to be construed as a critical,required, or essential features or elements of any or all the claims.The present invention is defined solely by the appended claims includingany amendments made during the pendency of this application and allequivalents of those claims as issued.

What is claimed is:
 1. A drug-delivering insertable medical device fortreating a medical condition associated with a body lumen of a bloodvessel, the body lumen comprising a plurality of layers, thedrug-delivering insertable medical device comprising: an outer surfacecoated with a plurality of nano-carriers having average diametersranging from 10 nm to 300 nm suitable for penetrating an adventitialayer of the blood vessel through the inter-tissue pores present in anintima layer of the blood vessel, a vasa vasorum associated with a medialayer of the blood vessel, and a vasa vasorum associated with theadventitia layer of the blood vessel; each nano-carrier comprising asirolimus drug surrounded by an encapsulating medium, the encapsulatingmedium comprising at least one of a biological agent, a blood excipient,and a phospholipid, a surface of each nano-carrier being devoid of thesirolimus drug; wherein the nano-carriers penetrating into theadventitia layer remain in the adventitia layer for a prolonged time andact as a reservoir of the sirolimus drug to slowly release the sirolimusdrug over a prolonged time; wherein the sirolimus drug diffuses acrossthe adventitia layer, the media layer and the intima layer during theprolonged time to provide an in-tissue diffusion of the sirolimus drugfor the prolonged time to supply a maximum portion of a lesion of theblood vessel with the sirolimus drug; and wherein the prolonged timecomprises 65 days.
 2. The drug-delivering insertable medical device ofclaim 1, wherein the at least one of a biological agent and thephospholipid has at least one effect selected from the group consistingof stabilizing the drug, and affinity for the target site.
 3. Thedrug-delivering insertable medical device of claim 1, wherein thedrug-delivering insertable medical device is one of a stent, a balloon,a stent mounted on a balloon, and a balloon catheter.
 4. Thedrug-delivering insertable medical device of claim 3, wherein thedrug-delivering insertable medical device is the stent mounted on theballoon, wherein at least a portion of the balloon extending beyond aproximal end of the stent and at least a portion of the balloonextending beyond a distal end of the stent are coated with the pluralityof nano-carriers.
 5. The drug-delivering insertable medical device ofclaim 3, wherein the stent and the balloon are coated with at least twolayers of the plurality of nano-carriers, wherein an outer layer of theat least two layers corresponding to the balloon and stent comprises atleast one nano-carrier with an average diameter to provide a burstrelease of a drug when the balloon is inflated upon coming in proximitywith the target site in the body lumen.
 6. The drug-deliveringinsertable medical device of claim 5, wherein the drug-deliveringinsertable medical device is coated with at least two layers ofnano-carriers, wherein the outer layer of the at least two layerscomprises at least one drug different from the sirolimus drug comprisedin the inner layer of the at least two layers.
 7. The drug-deliveringinsertable medical device of claim 5, wherein the outer layer ofnano-carriers comprises a drug selected from the group consisting of ananti-inflammatory agent, an anti-thrombogenic agent, and ananti-proliferative agent.
 8. The drug-delivering insertable medicaldevice of claim 5, wherein the outer layer of nano-carriers comprises adrug selected from the group consisting of an anti-proliferative agent,an anti-inflammatory agent, an anti-neoplastic agent, an anti-coagulantagent, an anti-fibrin agent, an antithrombotic agent, an anti-mitoticagent, an antibiotic agent, an anti-allergic agent and an antioxidant,an anti-proliferative agent, estrogens, a protease inhibitor,antibodies, an immunosuppressive agent, a cytostatic agent, a cytotoxicagent, a calcium channel blocker, a phosphodiesterase inhibitor, aprostaglandin inhibitor, a dietary supplement, vitamins, ananti-platelet aggregating agent and genetically engineered epithelialcells.
 9. The drug-delivering insertable medical device of claim 5,wherein the outer layer of nano-carriers comprises a drug selected fromthe group consisting of paclitaxel, sirolimus, tacrolimus, clobetasol,dexamethasone, genistein, heparin, 17 beta-estadiol, rapamycin,everolimus, ethylrapamycin, zotarolimus, ABT-578, Biolimus A9,docetaxel, methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, doxorubicin hydrochloride, mitomycin and analogs thereof,miomycine, sodium heparin, a low molecular weight heparin, a heparinoid,hirudin, argatroban, forskolin, vapiprost, prostacyclin, a prostacyclinanalogue, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole,glycoprotein IIb/IIIa, recombinant hirudin, bivalirudin, nifedipine,colchicines, lovastatin, nitroprusside, suramin, a serotonin blocker, asteroid, a thioprotease inhibitor, triazolopyrimidine, a nitric oxide ornitric oxide donor, a super oxide dismutase, a super oxide dismutasemimetic, estradiol, aspirin, angiopeptin, captopril, cilazapril,lisinopril, permirolast potassium, alpha-interferon, and bioactive RGD.10. The drug-delivering insertable medical device of claim 1, whereinthe biological agent is selected from the group consisting of excipientsderived from blood, phospholipids, lipoids, steroids, vitamins,estradiol, esterified fatty acids, non estrified fatty acid, glucose,inositol, L-lactate, lipoproteins, carbohydrates, tricalcium phosphate,precipitated calcium phosphate, calcium phoshate tribasic, andsubstances derived from human, egg and soybean.
 11. The drug-deliveringinsertable medical device of claim 1, wherein at least one of thebiological agent and the blood excipient dissolves in a medium having apH less than 7.4.
 12. The insertable medical device of claim 1, whereinthe medical condition comprises at least one of restenosis, blocked bodylumen, atherosclerosis, and plaque accumulation in the body lumen.